Effect of central administration of the kappa-opiate receptor agonist U 69.593 on neurohypophyseal hormone levels in blood and cerebrospinal fluid.

Intracerebroventricular (i.c.v.) administration of the kappa-opiate receptor agonist U 69.593 induces a rapid and short lasting suppression of oxytocin (OXT) levels in plasma of water deprived rats, whereas only a tendency towards a suppression of vasopressin (AVP) levels in plasma is observed. No change in neurohypophyseal hormone levels in CSF occurs following i.c.v. administration of U 69.593 at the various times points studied. It is concluded that, upon i.c.v. administration, the suppressive influence of U 69.593 is much weaker than that of the dynorphins and that neurophypophyseal hormone levels in CSF behave differently from those in the peripheral circulation.

The role of limbic vasopressin and oxytocin in social recognition.

Young male rats were exposed two times for 5 min, to older male rats with an interval of 30 min in the anti-vasopressin serum experiments and with an interval of 120 min in the anti-oxytocin serum experiments. The time spent by the older rats with social investigation of the younger animal was scored during the two encounters. In placebo-treated animals the time spent on social investigation of the younger animal during the second encounter at 30 min is significantly shorter than during the first one (social recognition). However, intracerebroventricular or local application of anti-vasopressin serum in the dorsal or ventral hippocampus or in the dorsal septal area, but not in the n. olfactorius, results in similar periods of time spent for social investigation during the two encounters. Thus, endogenous vasopressin in the dorsal and ventral hippocampus and in the dorsal septal region plays a physiological role in social recognition/memory. In placebo-treated rats the time spent on social investigation of the younger animal during the second encounter at 120 min is similar to that during the first encounter. However, local administration of anti-oxytocin serum in the ventral hippocampus, but not in the dorsal hippocampus, nor in the n. olfactorius or the septal area, results in shorter investigation times during the second encounter. Thus, taken together the presence or local release of vasopressin and oxytocin in the ventral hippocampus and that of vasopressin (but not oxytocin) in the dorsal hippocampus and dorsal septal area are of physiological importance for social recognition.

Dynorphin-A and vasopressin release in the rat: a structure-activity study.

The effects on vasopressin (VP) release of three dynorphin-A fragments and two antidynorphin antisera were tested in vivo and in vitro. In vivo, the order of potency to inhibit VP release 30 min upon i.c.v. injection was: dynorphin-A-(1-17) > dynorphin-A-(1-13) > dynorphin-A-(1-8). l.c.v. co-administration of 10 nmoles of the specific endopeptidase-inhibitor cFPAAF-pAB and dynorphin-A-(1-8) also suppressed VP secretion. Dynorphin-A-(1-17) antiserum enhanced VP release 20 and 60 min after i.c.v. injection. The antiserum that recognized dynorphin-A-(1-13) elevated VP plasma levels at 60 min post-injection. In vitro, dynorphin-A-(1-8) suppressed electrically evoked VP release from the isolated neural lobe. VP release was not affected by dynorphin-A-(1-13), dynorphin-A-(1-17), naloxone, or by the anti-dynorphin antisera. These data indicate that dynorphin-A-(1-17), rather than dynorphin-A-(1-8), plays a role in the centrally located control of neurohypophysial VP release, whereas dynorphin-A-(1-8) is involved in the control located in the posterior pituitary. The synthetic intermediate fragment dynorphin-A-(1-13) appears to affect VP release both centrally and peripherally.

Neuromedin-induced excessive grooming/scratching behavior is suppressed by naloxone, neurotensin and a dopamine D1 receptor antagonist.

Neuromedin B and neuromedin C were tested for their grooming/scratching-inducing effects and the composition of neuromedin-induced grooming was established by calculating the relative contribution of various grooming elements to the total grooming scores. Excessive grooming induced by neuromedins is characterized by a predominant display of scratching. Since neuromedin C is much more potent than neuromedin B to induce excessive grooming/scratching behavior, it is concluded that the carboxyl-terminal heptapeptide of neuromedin C is important for this effect. Furthermore, it is concluded that dopamine D1 receptors and opiate receptors are involved in this effect since the dopamine D1 receptor antagonist, SCH 23390, as well as the opiate receptor antagonist, naloxone, suppresses or attenuates neuromedin C-induced excessive grooming/scratching behavior.

Pharmacological assessment of the site of action of opioids on the release of vasopressin and oxytocin in the rat.

Naloxone and its congener, methyl naloxone, were given subcutaneously (s.c.) or centrally (i.c.v.) to 24-h water-deprived male rats 30 min prior to decapitation and the effect on plasma levels of vasopressin (VP) and oxytocin (OT) was studied. The potency of s.c. applied methyl naloxone to increase plasma OT levels did not differ from that of naloxone. Injected i.c.v., neither methyl naloxone nor naloxone had a clear effect and they antagonized i.c.v. co-administered dynorphin A-(1-13) equipotently. Methyl naloxone or naloxone, s.c., antagonized the inhibitory action of simultaneous dynorphin A-(1-13) and beta-endorphin-(1-31) given i.c.v., although higher doses of methyl naloxone were required. The data indicate that the sites of inhibition of neurohypophysial hormone release due to beta-endorphin-(1-31) are more likely to be located mostly within the blood-brain barrier, to which methyl naloxone has less ready access, than are the sites of inhibition due to dynorphin A-(1-13).

Neurohypophyseal hormones and excessive grooming behaviour.

The pattern of excessive grooming displayed by rats treated with vasopressin and oxytocin was investigated by calculating the frequencies and contribution of the behavioural elements head washing, body grooming, anogenital grooming, paw licking and scratching. In addition, the suppressive effect on peptide-induced grooming of the dopamine D1 receptor antagonist SCH 23390, of neurotensin and of the opiate receptor antagonists naloxone and naloxone-methobromide was studied. The pattern of excessive grooming induced by vasopressin and by oxytocin was characterized by the contribution of most behavioural elements to the total grooming scores. Oxytocin-induced excessive grooming was characterized by a marked increase in the frequency of anogenital grooming. SCH 23390, neurotensin and naloxone, but not naloxone-methobromide, suppressed excessive grooming induced by vasopressin and oxytocin. It is suggested that dopamine D1 receptors as well as opiate receptors located within the blood-brain barrier are involved in the excessive grooming induced by neurhypophyseal hormones.

Dopamine D-1 and D-2 receptor agonists and antagonists and neuropeptide-induced excessive grooming.

The administration of the dopamine D-1 receptor antagonist, SCH 23390, but not of the dopamine D-2 receptor antagonist, sulpiride, suppressed the excessive grooming induced by a new environment or by various neuropeptides. In addition, administration of the dopamine D-1 agonist, SK & F 38393, induced excessive grooming but that of the dopamine D-2 agonist, quinpirole, did not. It is suggested that dopamine D-1 rather than D-2 receptor stimulation is an important mechanism underlying novelty-induced as well as neuropeptide-induced excessive grooming.

Grooming behavior induced by substance P.

The intracerebroventricular (i.c.v.) administration of substance P elicits in rats an excessive grooming that is characterized by body grooming, anogenital grooming and scratching. The total grooming scores displayed by rats treated with substance P hardly exceeded 23% of the theoretical maximal grooming score. Substance P-induced excessive grooming was suppressed by pretreatment with naloxone, haloperidol on neurotensin. It is concluded that substance P induces excessive grooming with a pattern different from that of grooming elicited by other peptides.

Some characteristics of TRH-induced grooming behavior in rats.

Intracerebroventricular administration of TRH induces excessive grooming behavior that is characterized by an important contribution of the elements scratching and paw licking. As compared with other grooming inducing peptides, the pattern of TRH-induced grooming resembles that induced by beta-endorphin rather than those elicited by ACTH or bombesin. TRH-induced excessive grooming is suppressed by pretreatment with haloperidol, naloxone or neurotensin. Haloperidol suppresses TRH-induced grooming in a general way, whereas the suppressive effect of the other drugs is mainly due to a selective reduction of TRH-induced excessive scratching. Combined treatments of rats with TRH and a submaximal dose of ACTH, bombesin or beta-endorphin do not result in higher grooming scores than with single peptide treatment. Excessive grooming elicited by water immersion is not affected by TRH. It is concluded that TRH is undoubtedly an excessive grooming inducing peptide. In situations where excessive grooming is elicited by other peptides or by water immersion, TRH does not further activate the operating systems involved in the existing excessive grooming.

Excessive grooming induced by somatostatin or its analog SMS 201-995.

Intracerebroventricular (i.c.v.) administration of somatostatin or SMS 201-995 induces excessive grooming behavior in rats. The grooming inducing effect of somatostatin is rather weak, as doses of 300 ng or less did not result in increased total grooming scores. In contrast a dose of 10 ng SMS 201-995 already significantly increased the total grooming scores. However, doses of 100 ng and more did not further increase the total grooming scores reached with a 50 ng dose of this peptide. Systemic administration of SMS 201-995 in doses up to 900 micrograms did not result in excessive grooming behavior. The patterns of excessive grooming induced by i.c.v. SMS 201-995 and somatostatin were characterized by a predominant display of scratching. Since peptide-induced scratching is mainly due to activation of opiate receptor systems it is suggested that opiate receptors are involved in the behavioral response to SMS 201-995 and somatostatin administration. This suggestion is further supported by the suppressive effect of naloxone on excessive grooming induced by these peptides. Haloperidol and neurotensin also suppress the excessive grooming induced by somatostatin but not that induced by SMS 201-995. Finally, tolerance developed to the grooming-inducing effect of SMS 201-995 and somatostatin. In addition there was cross tolerance between somatostatin and SMS 201-995.

Dynorphin-(1-13) is a potent in vivo suppressor of vasopressin levels in the rat.

Intracerebroventricular administration of dynorphin-(1-13) inhibits dose-dependently plasma vasopressin level in normal as well as in water-deprived rats, whereas systemic (subcutaneous) administration of this opioid peptide is ineffective in this respect. Simultaneous subcutaneous, but not intracerebroventricular, administration of naloxone prevents the suppressive effect of dynorphin-(1-13) on plasma vasopressin levels.

The influence of neurotensin, naloxone, and haloperidol on elements of excessive grooming behavior induced by ACTH.

Naloxone, haloperidol, and neurotensin suppress ACTH-induced grooming. The suppressive effects of naloxone and of haloperidol on ACTH-induced grooming are observed following subcutaneous as well as intracerebroventricular administration. The suppression of ACTH-induced grooming by these drugs is not accompanied by a change in the relative distribution of grooming elements. From previous data and from the results of the present study it is suggested that the underlying substrate involved in ACTH-induced excessive grooming may differ from that of bombesin-induced grooming.

Effect of the opioid peptide beta-endorphin on the in vivo release of vasopressin in rats under various conditions.

beta-Endorphin (beta E) exerts a strong inhibitory action on plasma vasopressin (VP) of rats, after intracerebroventricular, but not after subcutaneous injection of the drug. This effect is time- and dose-dependent. Also in the water-deprived rat, this treatment leads to a strong decrease of plasma VP levels. When rats treated with histamine (HIS) intracerebroventricularly to stimulate VP levels are injected with beta E to HIS treatment, beta E partially prevents the increase of plasma VP levels. Naloxone subcutaneously administered, antagonizes the effect of beta E in all the situations we investigated. Opioid receptors, located in the brain as well as in the pituitary, are possibly involved in these processes.

The effects of neurotensin, naloxone and haloperidol on elements of excessive grooming behavior induced by bombesin.

The influence of naloxone, haloperidol and neurotensin was investigated on bombesin-induced excessive grooming in rats. All three drugs reduced the amount of bombesin-induced grooming. Haloperidol induced a general reduction in excessive grooming as induced by bombesin, without changing the composition of grooming behavior, whereas naloxone and neurotensin suppressed bombesin-induced grooming and caused a shift in the distribution of grooming elements. The main suppressive effect of these latter drugs appeared to be on the element scratching. From these data it is suggested that bombesin-induced scratching is mainly displayed by activation of opiate receptor systems, whereas the other elements of bombesin-induced excessive grooming are mainly regulated by dopaminergic systems.

Comparison between excessive grooming induced by bombesin or by ACTH: the differential elements of grooming and development of tolerance.

Bombesin and ACTH-(1-24) induce a dose dependent increase in grooming behavior. Lower doses of bombesin induce a more general type of compulsive grooming in which most elements are involved, whereas higher amounts of bombesin induce a shift towards the element scratching at the cost of bodily grooming and sexual grooming. In contrast ACTH-(1-24) induces a dose dependent increase of all elements of grooming. It is concluded that the grooming displayed by animals treated with ACTH-(1-24) or with bombesin is of a completely different nature. In addition it is observed that under the conditions used tolerance occurs for the grooming inducing effect of ACTH-(1-24), but not for that of bombesin. Moreover, it appears that no cross tolerance exists between bombesin and ACTH-(1-24).